Rxivist logo

C. elegans granulins promote an age-associated decline in protein homeostasis via lysosomal protease inhibition

By Victoria J. Butler, Wilian A Cortopassi, Andrea R Argouarch, M. Olivia Pierce, Mihir Vohra, Juan A. Oses-Prieto, Fuying Gao, Benjamin Caballero, Shreya Chand, William W Seeley, Bruce L. Miller, Giovanni Coppola, Alma L Burlingame, Kaveh Ashrafi, Ana Maria Cuervo, Matthew P. Jacobson, Aimee W. Kao

Posted 17 Nov 2018
bioRxiv DOI: 10.1101/472258

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases (or cathepsins) are key contributors to maintenance of protein homeostasis with age. Here, we identify the cysteine-rich granulin peptides as a new class of regulators of lysosomal aspartyl protease activity. Granulins are produced in an age and stress-dependent manner through cleavage of the neurodegenerative disease protein, progranulin. Once liberated, granulins selectively interact with the aspartyl protease ASP-3/cathepsin D to impair enzymatic activity. Consequently, protein homeostasis and lysosome function is disrupted, prompting cells to activate a compensatory transcriptional program. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

Download data

  • Downloaded 510 times
  • Download rankings, all-time:
    • Site-wide: 35,626 out of 101,301
    • In neuroscience: 6,093 out of 18,046
  • Year to date:
    • Site-wide: 63,714 out of 101,301
  • Since beginning of last month:
    • Site-wide: 64,876 out of 101,301

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News

  • 20 Oct 2020: Support for sorting preprints using Twitter activity has been removed, at least temporarily, until a new source of social media activity data becomes available.
  • 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
  • 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
  • 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
  • 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
  • 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
  • 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
  • 22 Jan 2019: Nature just published an article about Rxivist and our data.
  • 13 Jan 2019: The Rxivist preprint is live!